Hepatocellular carcinoma (HCC) is a major global health problem with >626,000 new cases per year worldwide. In North America, Asia, and Europe it is the third highest cause of cancer-related death, behind lung and colon cancer. A rise in the incidence and mortality of HCC has been observed in most industrialized nations over the past three decades. It probably reflects the increasing prevalence of hepatitis C virus infection in these countries. In the West, the disease is diagnosed at early stages in 30-40% of all patients and is amenable to potentially curative treatments, such as surgical therapies and locoregional procedures. Nevertheless, HCC remains a poorly treated cancer which afflicts more than half million people each year with survival rates of only 23% and <5% at 1 and 5 years, respectively. One reason for the high mortality rate is that treatment options are limited with few chemotherapeutic regimens currently approved for the treatment of unresectable HCC.
HCC is developed through cirrhosis brought on by chronic liver injury. This chronic injury results in fibrogenesis that damages the normal liver circulatory system and leads to the shortage of blood perfusion and oxygen delivery in the liver. Moreover, in tumor tissues, a high rate of cell proliferation in the tumor cells as well as abnormalities of structure and function associated with tumor vessels increases the need for oxygen. Through the activation of hypoxia inducible factor-1, hypoxia enhances proliferation, angiogenesis, metastasis, chemo- and radioresistance of HCC; it also suppresses cellular differentiation and apoptosis. Treatment of HCC by transarterial embolization also contributes to angiogenesis via hypoxia induction. Since angiogenesis plays an important role in recurrence of HCC after surgical resection, hypoxia targeting agents are becoming important tools in combinational therapy of this disease.
Nordihydroguaiaretic acid (NDGA, 1, FIG. 1) is a lipoxygenase inhibitor and anti-oxidation agent isolated from a desert medicinal plant, the Creosote bush (Larrea tridentate). In 2005, it was reported that tetra-O-methyl nordihydroguaiaretic acid (2, FIG. 1) can suppress the growth of a variety of mouse and human tumor cells as well as human tumor explants in nude mice. The development of this compound was prompted by the earlier discovery of naturally occurring 3-O-methyl nordihydroguaiaretic acid, which can inhibit HIV-1 viral replication by inhibiting the binding of transcription factor Sp1 to its cognate binding sites on the HIV long-terminal repeat promoter. The tetra-O-methylated NDGA derivative was subsequently synthesized and found to have similar Sp1 inhibitory activity.
In hypoxic cells, nitroimidazoles undergo a series of enzymic reductions, mediated by nitroreductase enzymes, and followed by ring fragmentation. Reactive radicals are thus generated, which then irreversibly bind to the cellular components. After the drugs enter the cell by passive diffusion, reduction enables more drugs to accumulate in the cell by a favorable concentration gradient as reduction proceeds intracellularly. In normoxic cells, the presence of oxygen prevents the enzymic reduction of nitroimidazole, and hence no binding occurs. In addition, nitroimidazoles show preferential toxicity to hypoxic cells as hypoxic cytotoxins. Their cytotoxicity toward hypoxic cells is a result of abstraction of hydrogen from target molecules by free radicals formed in the reduction of the nitro group.
There still exists an unmet need for novel nitroimidazole compounds that are useful for treating HCC and other cancers.